This invention relates to certain N-alkyl, N,N-dialkyl, and N,N,N-trialkyl derivatives of thienamycin sulfoxide (n=1) and thienamycin sulfone (n=2): ##STR2## wherein n=1 or 2 and R.sup.5, R.sup.6 and R.sup.7 are independently selected from hydrogen or alkyl; R.sup.5, R.sup.6 and R.sup.7 are defined more fully below. Such compounds (I) and their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics.
This invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Thienamycin is disclosed and claimed in U.S. Pat. No. 3,950,357 issued Apr. 13, 1976; said application is incorporated herein by reference since thienamycin may serve as the starting material in the preparation of the compounds of the present invention. Thienamycin is known to have the following structural formula (1): ##STR3##
Thienamycin and all of its isomers (in pure form and as mixtures) are also obtainable by the total synthesis disclosed and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 792,071 (filed 28 Apr. 1977, now abandoned in favor of U.S. patent application Ser. No. 833,210, filed Sept. 15, 1977). This application is incorporated herein by reference to the extent that it makes available all isomers of 1 as starting materials in the preparation of the compounds of the present invention. Additionally incorporated by reference is co-pending commonly assigned U.S. patent application Ser. No. 734,584 (filed Oct. 21, 1976, now abandoned in favor of U.S. patent application Ser. No. 893,848, filed Apr. 6, 1978 as Merck & Co., Inc.) which discloses and claims two distinct isomeric forms of 1 which are antibiotics and which are isolated, as N-acetyl derivatives, as natural products of fermentation.
Also incorporated by reference are U.S. patent applications Ser. No. 821,679 filed Aug. 4, 1977, now abandoned, and its continuation-in-part application Ser. No. 833,620 filed Sept. 15, 1977, concurrently with the present application (Merck & Co., Inc.) and 733,611 filed Oct. 18, 1976, now abandoned in favor of U.S. patent application Ser. No. 861,235, filed Dec. 16, 1977 which disclose and claim, respectively, thienamycin sulfoxide and thienamycin sulfone (2) and N-alkylated derivatives of thienamycin (3): ##STR4## wherein, relative to 3, R.sup.3, X, R, R.sup.5, R.sup.6, and R.sup.7 are the same as defined below for the compounds of the present invention (I). These applications are incorporated herein by reference since the first-described (and its continuation-in-part) provides procedures for preparing the sulfoxide/sulfone and the second provides the useful starting materials 3 which are oxidized according to the procedures of the first-mentioned application to provide the compounds of the present invention (I).
Other convenient starting materials for the N-alkylated thienamycin sulfoxides of the present invention are shown below (Ia, Ib, and Ic). (Actually, Ia, Ib, Ic are used to prepare 3, which in turn is used to prepare I): ##STR5## wherein R.sup.3, X and R are defined below. Starting materials Ia, Ib, and Ic, which are also useful as antibiotics, are disclosed and claimed in co-pending concurrently filed U.S. patent applications Ser. Nos. 733,655, 733,651 and 733,652, respectively; all filed Oct. 18, 1976, all now abandoned in favor of U.S. patent applications Ser. Nos. 861,234, 861,314 and 861,246, respectively, all filed Dec. 16, 1977. These applications are incorporated herein by reference since they describe useful starting materials and/or processes for converting the N-alkylated thienamycins to carboxyl-, O-; and carboxyl- and O-derivatized forms which are also embraced by the present invention.
The N-alkylated thienamycin sulfoxide/sulfone derivatives of the present invention may be depicted by the following generic structural formula: ##STR6## n is 1 or 2; M is H, a salt cation selected from alkali or alkaline earth metals or an amine salt; and
R.sup.5, r.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen (not all of R.sup.5, R.sup.6 and R.sup.7 are hydrogen at the same time) substituted and unsubstituted: lower alkyl having 1-10 carbon atoms, alkenyl having 2-10 carbon atoms, alkynyl having 2-10 carbon atoms, ring substituted and unsubstituted: cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl having 3-6 ring carbon atoms and 1-6 carbon atoms in the alkyl chain, aryl having 6-10 carbon atoms, aralkyl having 6-10 ring carbon atoms, and 1-6 carbon atoms in the alkyl chain, mono- and bicyclic heteroaryl and heteroaralkyl comprising 4-10 ring atoms one or more of which is selected from oxygen, nitrogen and sulphur and 1-6 l carbon atoms in the alkyl chain; and wherein the ring or chain substituent is selected from: halo such as chloro, bromo, iodo and fluoro, azido, cyano, amino, mono-, di and trialkyl substituted amino wherein the alkyl has 1-6 carbon atoms; hydroxyl, alkoxyl having 1-6 carbon atoms; alkylthioalkyl having 1-6 carbon atoms; carboxyl; oxo; alkoxylcarbonyl having 1-6 carbon atoms in the alkoxyl moiety; acyloxy comprising 2-10 carbon atoms; carbamoyl, and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms; cyanothio (--SCN); and nitro. It will be recognized that the N,N,N-trialkyl derivatives are quaternary ammonium compounds, the counter ion (anion) of which is not critical and may be selected from halides, such as chloro and bromo, phosphate, sulphate and the like. PA1 R.sup.3 is (1.) acyl (generically the group OR.sup.3 is classifiable as an ester); or (2.) R.sup.3 is selected from alkyl, aryl, aralkyl and the like (such that the group OR.sup.3 is generically classifiable as an ether). R.sup.3 may also be hydrogen. The term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur; as well as sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl-, and sulfenyl-radicals, and substituted P(III and V) radicals such as substituted phosphorous-, phosphoric-, phosphonous- and phosphonic-radicals, respectively. Such acyl radicals of the present invention are further defined below, as are the radicals (2., above) which constitute the ether embodiments of the present invention. PA1 (i) R=CR.sup.a R.sup.b R.sup.c wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-donor, e.g., p-methoxyphenyl, 2,4,6-trimethylphenyl,9-anthryl,methoxy, CH.sub.2 SCH.sub.3, tetrahydrofur-2-yl, tetrahydropyran-2-yl or fur-2-yl. The remaining R.sup.a, R.sup.b and R.sup.c groups may be hydrogen or organic substituting groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl. PA1 (ii) R=CR.sup.a R.sup.b R.sup.c wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-attracting group, e.g., benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethylsulphoniummethyl, o-nitrophenyl or cyano. Suitable esters of this type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl. PA1 (iii) R=CR.sup.a R.sup.b R.sup.c wherein at least two of R.sup.a, R.sup.b and R.sup.c are hydrocarbon such as alkyl, e.g., methyl or ethyl, or aryl, e.g., phenyl and the remaining R.sup.a, R.sup.b and R.sup.c group, if there is one, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl. PA1 (iv) R=R.sup.d, wherein R.sup.d is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl or tetrahydropyran-2-yl. PA1 R.sup.4.sub.3 siX'; R.sup.4.sub.2 SiX'.sub.2 ; R.sup.4.sub.3 Si.NR.sup.4.sub.2 ; R.sup.4.sub.3 Si.NH.COR.sup.4 ; PA1 R.sup.4.sub.3 si.NH.CO.NH.SiR.sup.4.sub.3 ; R.sup.4 NH.CO.NH.sup.4.SiR.sup.4.sub.3 ; or R.sup.4 C(OSiR.sup.4.sub.3); PA1 Hn(siR.sup.4.sub.3).sub.2 wherein X' is a halogen such as chloro or bromo and the various groups R.sup.4, which can be the same or different, represent hydrogen atoms or alkyl, e.g., methyl, ethyl, n-propyl, iso-propyl; aryl, e.g., phenyl; or aralkyl, e.g., benzyl groups. PA1 --N(R).sub.2 and --N.sup.+ (R).sub.3
The compounds of the present invention also embrace embodiments of the following structure: ##STR7## wherein the basic symbolism is as previously defined and X is oxygen, sulphur or NR' (R'=H or R); and R is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in the bicyclic .beta.-lactam antibiotic art; the definition of R is given in greater detail below;
There is a continuing need for new antibiotics. For, unfortunately, there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of the antibiotic thienamycin but which are characterized as N-alkylated derivatives thereof. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, S. pyogenes and B. subtilis and gram negative bacteria such as E. coli, Proteus morganii and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts, pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.